Stiffening of central arteries (i.e., the aorta and carotids) is now recognized as a strong indicator and initiator of cardiovascular, neurovascular, and renovascular diseases. Active searches are underway both to identify the best clinical metric of increased arterial stiffness and to find de-stiffening drugs that can lower disease ris. Amongst the metrics considered, carotid-femoral pulse wave velocity (cf-PWV) has emerged as the gold standard for assessing stiffness and the potential efficacy of de-stiffening drugs. Yet, given that arteries stiffen differentially by region and that cf-PWV yields information that is necessarily averaged over a large portion of the central vasculature, we submit that there is a need to assess better its potential as an early indicator of arterial stiffening. That is, it may b that by the time cf-PWV increases to a diagnostic value, underlying structural and mechanical changes may be largely entrenched and thereby less amenable to treatment. The goals of this project are to build on a very successful first 4-year funding period (25 papers + 10 expected soon) and to quantify and compare, for the first time, the progression of regional differences in large artery stiffening in four diverse mouse models that collectively address four key aspects of human hyper- tension, namely, endothelial dysfunction, effects of salt loading, and excess systemic vs. local angiotensin-II. These models also depend, in part, on inflammation, which is increasingly recognized as an important contributor to hypertension and vascular aging. Progressive, regional, stiffening of 5 arteries (carotid, descending thoracic, suprarenal abdominal, infrarenal abdominal, and iliac) will be quantified via in vivo data as well as novel computer-controlled in vitro biaxial tests. These data, in turn, will be used to extend and inform novel fluid-solid-interaction computational model that will be validated with available data and then used to assess the effects of evolving regional differences in wall properties on cf-PWV and, importantly, the pulse pressures at the levels of the heart and kidney. It is, of course, the increased pulse pressures in the coronary and renal vasculature that is the true concern of hypertension. Finally, we will also assess the potential efficacy of two drugs, an angiotensin-II type 1 receptor antagonist and an anti-inflammatory agent, again using the most comprehensive structural, mechanical, and hemodynamic assessments to date. This project is highly significant for it will reveal unprecedented insight into fundamental structural and mechanical mechanisms that underlie central arterial stiffening and its effects on central hemodynamics, which is increasingly important to large segments of our society - hypertensive, the elderly, diabetics, the obese, transplant recipients, and even those treated for AIDS. This project is innovative for i will couple novel experimental methods and computational models to study together four different mouse models that represent a broad spectrum of contributors to human hypertension as well as the efficacy of two potential treatments of both.